A problem of an increasing incidence rate of such musculoskeletal diseases as osteoporosis, osteoarthritis, and osteochondrosis is becoming increasingly relevant. This is reflected by numerous publications devoted to this subject. Despite of efforts being taken by experts in different areas, this problem is far from being resolved.
Osteoporosis is the most common human bone disease. This is a chronic systemic disease characterized by lowering bone mass and progressing deterioration of bone tissue microarchitecture, which can lead to decreased bone strength and increased risk of pathologic fracture. Now, osteoporosis is classified into two basic types which are primary and secondary one. Drugs used for osteoporosis treatment are bone resorption inhibitors (estrogens, selective estrogen receptor modulators, selective tissue estrogenic activity regulators, calcitonins, bisphosphonates and other drugs (odanacatib, denosumab, etc.)); osteogenesis stimulators (fluorides, somatotropic hormone, anabolic steroids, androgens); multifunctional drugs (strontium ranelate, active metabolites of ergocalciferol, ossein-hydroxyapatite compound).
Problem of the osteoporosis treatment is still of topic issue despite the wide range of approved drugs. Severe adverse reactions induced by prolonged drug administration and poor compliance to prolonged treatment are the major disadvantages of the existing treatment.
Osteoarthritis (OA) is considered an organ lesion, i.e, an entire joint disorder when a pathological process involves all the joint components: cartilage, subchondral bone plate, synovial membrane, ligaments, capsule, and muscles.
Osteoarthritis treatment is still seeking to resolve the disease symptoms, i.e., pain relief, improving the joint functionality and arresting the pathology progression. A symptomatic effect is achieved by a combination of non-pharmacological and pharmacological methods set out in numerous guidelines. In most cases, the existing treatment methods do not achieve joint tissue neogenesis, arrest of pathology progression or at least long-term and steady slowdown in the disease progression.
Thus, we need to develop new effective drugs along with other methods of treatment for musculoskeletal diseases related to the disorder of bone and/or cartilage metabolism such as osteoporosis, osteoarthritis, and osteochondrosis. Modulation of intracellular signaling pathways is considered to be one of the most interesting trends.
Protein kinases are protein family critical for regulation of key cellular processes; disorders in activity of these proteins can result in various diseases. A promising approach to treatment of diseases associated with abnormal activity of protein kinases is using low-molecular weight compounds to inhibit activity thereof. Examples of such inhibitors approved for clinical practice are: imatinib, nilotinib, dasatinib, sunitinib, sorafenib, lapatinib, gefitinib, erlotinib, crizotinib. Lots of drug candidates being kinase inhibitors are under clinical trial stage or preclinical stage now.
c-Src kinase (Proto-oncogene tyrosine-protein kinase) is a non-receptor tyrosine kinase involved in processes of embryogenesis and cell growth. Inhibition of c-Src kinase was demonstrated to block actin ring formation and prevent osteoclast-mediated bone destruction in various in vitro models. Furthermore, c-Src kinase is involved in signaling pathway leading to hypertrophic changes in chondrocytes associated with aberrant cartilage metabolism, which is characteristic for diseases related to dystrophic degeneration processes in this tissue.
It has been demonstrated earlier, that saracatinib is a new competitive inhibitor of Src kinase, which inhibits resorption of bone tissue in vitro. In the course of phase I clinical trials, it was established that saracatinib inhibits osteoclast-mediated resorption of bone tissue in healthy men without any adverse events (R. A. Hannon, G. Clack, M. Rimmer et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, doubleblind, placebo-controlled, multiple ascending dose phase I trial.//J Bone Miner Res. 2010. V. 25. No. 3. P. 463-71.). However the further clinical trials showed that high toxicity of saracatinib at daily exposure of a therapeutically effective dose makes it impossible to use this drug in clinical practice for the musculoskeletal disease treatment.
Thus, inhibition of c-Src kinase is a highly promising strategy of managing osteoporosis, osteoarthritis and other musculoskeletal diseases, which pathogenesis is related to the bone and cartilage aberrant metabolism.
However, drugs based on Src kinase inhibitors are not available now in the clinical practice of musculoskeletal disease treatment. Thus, a task arises to research and develop new effective drugs, i.e., c-Src kinase inhibitors, for treatment of osteoporosis, osteoarthritis and other musculoskeletal diseases.